The work of our and other laboratories have implicated variations in 1) quantity of glucocorticoid receptors, 2) developmental patterns of cyclic AMP concentrations in palatal shelves, and/or 3) rates of growth and ultimate dimensions of facial structures as etiologically important in the causation of murine, steroid-induced cleft palate. Although "abnormalities" of these variables have been suggested to be causal in the pathogenesis of cleft palate, the evidence to present rests on the association of differences in these variables with strains of mice with high or low palate susceptibility; there has been no experimental test of cause and effect. We propose to perform a close approximation for such a test by the use of recombinant inbred (R.I.) lines between the C57BL6/J and the A/J strains. These lines, developed by Dr. Muriel Nesbitt, provide 40 inbred strains of mice in which the genomes of the A/J and C57BL6/J strains have been nearly randomly mixed (segments of about 5 centimorgans are expected to remain intact, which is useful for linkage studies). We propose to measure variation in 1) hepatic glucocorticoid receptor levels, 2) palatal shelf cyclic AMP concentrations at critical stages of palatal shelf fusion, 3) mandibular dimensions generating morphometric indices for the two strains and relate these 3 major variables to steriod-induced cleft palate incidence in a number of these recombinant inbred lines. The associations of each of these variables with one another and with cleft palate susceptibility will be thus tested in material in which multiple associations of the same variables with one another and with cleft palate susceptibility are extremely unlikely to occur by chance (given the number of R.I. lines available). This approach is the strongest approach available to test causal hypotheses on complex in vivo developmental pathways which are under genetic control. We will also study 1) the possible segregation of cleft lip/palate, 2) the incidence of 6-aminonicotinamide-induced cleft palate and diphenulhydantoin-induced cleft lip/palate (which differ in incidence between the A/J and C57B liter/CJ strains) and 3) relevant genetic markers such as H-2 and ones linked to H-3 in these R.I. lines to determine possible etiological interactions.